Quinazolinylureas

ABSTRACT

1-(2-DIMETHYLAMINO)-6,7-DIMETHOXY-4-QUINAZOLINYL)3-METHYLUREA AND SIMILAR 1-(2-AMINO-4-QUINAZOLINYL)UREAS ARE HYPOTENSIVE AGENTS. REACTING ALKYL ISOCYANATE WITH A 2-AMINO-4-(UNSUBSTITUTED AMINO)QUINAZOLINE AFFORDS THE 1-(4-QUINAZOLINYL)-3-ALKYLUREAS; REACTING A 2-AMINO-4-(UNSUBSTITUTED AMINO)QUINAZOLINE WITH INORGANIC CYANATE AND HYDROCHLORIC ACID AFFORDS THE 1-(4-QUINAZOLINYL)UREA.

United States Patent O M 3,574,212 QUINAZOLINYLUREAS Hans-Jurgen Hess, Groton, Conn, assignor to Pfizer Inc., New York, N.Y. N Drawing. Filed Feb. 2, 1968, Ser. No. 702,534 Int. Cl. C07d 51/48 US. Cl. 260256.4 6 Claims ABSTRACT OF THE DISCLOSURE 1-[2- (dimethylamino) '6,7-dimethoxy-4-quinazolinyl1- 3-methylurea and similar l-(2-amino-4-quinazo1inyl)ureas are hypotensive agent. Reacting alkyl isocyanate with a 2-amino-4-(unsubstituted amino)quinazoline aflords the 1-(4-quinazolinyl)-3-alkylureas; reacting a 2-amino-4-(unsubstituted amino)quinazoline with inorganic cyanate and hydrochloric acid alfords the 1-(4-quinazolinyl)urea.

BACKGROUND OF THE INVENTION This invention relates to novel chemotherapeutic agents; in particular, it relates to certain novel quinazolinylureas which are useful as hypotensive agents.

SUMMARY OF THE INVENTION The novel compounds of the instant invention are quinazolinylureas of the formulae R and R are each selected from the group consisting of hydrogen, alkyl having from 1 to carbon atoms, alkenyl having from 3 to 5 carbon atoms, hydroxylalkyl having from 2 to 5 carbon atoms, phenyl, benzyl, phenylethyl, 2-furfuryl, 2,2,2,-trifluoroethyl and cycloalkyl having from 3 to 8 carbon atoms;

R is H or alkyl having from 1 to 6 carbon atoms;

R and R are each selected from hydrogen and alkoxy having from 1 to 3 carbon atoms, at least one of R and R being alkoxy;

Z is selected from the group consisting of morpholino,

l-azacycloheptyl, l-azacyclooctyl;

piperazino of the formula:

Where Y is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, hydroxyalkyl where alkyl has from 2 to 5 carbon atoms, alkanoyl having from 2 to 7 carbon atoms, allyl, propargyl, 2-methylallyl, phenyl, benzyl, benzoyl, halobenzoyl and halophenyl where halo is chloro or bromo,

3,574,212 Patented Apr. 6, .1971

trifluoromethylphenyl, methoxyphenyl, methylphenyl. methylbenzoyl, methoxybenzoyl, trifiuoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl, 3, 4,5-trimethoxybenzoyl, carboxylic acid alkyl ester where alkyl has from 1 to 6 carbon atoms, carboxylic acid alkenyl ester where alkenyl has from 3 to 6 carbon atoms;

piperidino of the formula:

acid alkyl ester where alkyl has from 1 to 6 carbon atoms when X' is phenyl.

These quinazolinylureas are efiective hypotensive agents and may be administered for this purpose as the free base or pharmaceutically-acceptable acid addition salt, either alone or with a pharmaceutically-acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION The instant compounds wherein R is alkyl are readily prepared from 4-aminoquinazolines of the formulae wherein R R R R and Z are as aforesaid. These 4-aminoquinazolines may be obtained by methods disclosed in U.S. patent application Ser. No. 555,704, filed June 6, 1966 (now abandoned).

Treating said 4-aminoquinazolines with alkyl isocyanate R3-NCO results in the formation of the desired compound of Formula I or II wherein R is alkyl containing up to 6 carbon atoms. For best results, a substantial excess of the alkyl isocyanate should be used. The reaction is preferably conducted in a pressure vessel when the alkylisocyanate has a low boiling point, for example methyl isocyanate, in order to prevent loss of this reagents. With higher boiling isocyanates, the need for a pressure vessel is not as urgent and it may be dispensed with entirely where the boiling point is sufiiciently high. Common reaction-inert organic solvents may be used, such as benzene, toluene, pyridine and triethylamine. However, inasmuch as the reaction proceeds best in the presence of base, basic solvents such as pyridine and triethylamine are preferred. Neither reaction time nor temperature is critical. When using a pressure vessel, temperatures between room temperature and about C. are efiective; when a pressure vessel is not used, with higher alkyl isocyanates, temperatures between room temperature and reflux are appropriate. Reaction times up to about 24 hours are adequate; of course a higher reaction temperature will permit the use of shorter times Without a loss of product. With methyl isocyanate, for example, running the reaction for about 4-10 hours at about 100 C. has typically resulted in satisfactory yields.

The products are isolated from the reaction mixture by standard procedures familiar to those skilled in the art, for example, precipitation, removal of solvent, extraction and the like.

When compounds of Formulae I and II, wherein R is alkyl, have R or R as hydrogen or R R or Z containing a hydroxyl group, aforesaid reaction with alkyl isocyanate is not preferred since these substituents would be expected to react with the isocyanate reagent. A preferred synthesis of these compounds is the conversion of a 2-chloro-4-aminoquinazoline to 1- (2-ch1oro- 4 quinazolinyl) 3 alkylurea by treatment with alkyl isocyanate, followed by replacement of the 2-chloro group with the specific amino group desired, according to the The various 2-chloro-4-aminoquinazolines are obtained by methods disclosed in aforesaid application Ser. No. 555,704. The reaction with alkyl isocyanate is conducted under the same conditions of time, temperature, pressure and substrate ratio as aforesaid treatment of 4-aminoquinazolines with alkyl isocyanate. The resulting 1-(2- chloro-4-quinazolinyD-3aalkylurea is most easily converted to the various 1-(2-arnino-4-quinazolinyl)-3-alkylureas by heating a solution or suspension of the chloro material with the appropriate amine, e.g. heating with ethylamine results in the formation of a Z-ethylarrfino-quinazoline. An ethanolic solution of the amine may conveniently be used for suspending the chloro material and temperatures between about 100 C. and 180 C. are adequate. Heating for up to about 24 hours is usually sufficient. The final material is easily isolated by evaporating the excess solvent .and amine and recrystallizing the product.

Preparation of compounds of Formulae I and II wherein R is hydrogen is accomplished by reacting a 2-amino-4- (unsubstituted amino)quinazoline with an inorganic cyanate and hydrochloric acid. Ammonium cyanate, sodium cyanate and potassium cyanate are suited for this purpose. At least equimolar amounts, with respect to the quinazoline, of cyanate and hydrochloric acid are preferably used, and more preferably, at least a molar excess of each Will be used.

The reaction is conveniently conducted by adding the reagents to an aqueous suspension of the quinazoline. Neither reaction time nor temperature is critical, and the reaction may be conducted between about room temperature and reflux, with the necessary time to obtain satisfactory yields being dependent upon the temperature. It has been found that warming the aqueous reaction mixture on a steam bath for one hour afiords a satisfactory yield of the product, which may then be isolated and purified by standard techniques such as solvent removal, crystallization, extraction and the like.

Compounds of Formulae I and 11 wherein R is hydrogen can also be prepared from aforesaid 2-chloro- 4-alminoquinazolines when the reactivity of a particular amino moiety at the 2-position might interfere with the desired conversion, according to the sequence The novel quinazolinylureas of the instant invention are efiective hypotensive agents in animals, and are thereby useful in alleviating high blood pressure in hypertensive subjects. 'For this purpose, these compounds are administered by standard methods familiar to those skilled in the art. Preferred agents are those wherein R and R are each methoxy, in particular 1-[2 (4-{2-furoyl}-1- piperazinyl)-6,7-dimethoxy 4 quinazolinyl1-3 methylurea, l-[2-(dimethylamino)-6,7 dimethoxy 4 -quinazolinyl] 3 methylurea,l-[Z-(4-allyl-l-piperazinyl)6,7- dimethoxy 4 quinazolinyl]-3-methylurea and 1-[2-(4- carboisobutoxy-l-piperazinyl)-6,7-dimethoxy-4 quinazolinyl] -3-methylurea.

The instant compounds may be conveniently administered in the form of pharmaceutically-acceptable salts. By "pharmaceutically-acceptable is meant those salts which do not have substantially greater toxicity than the free compound. The pharmaceutically acceptable acid ad-- dition salts inlude salts of mineral acids such as hydrochloric, hydrobromic, hydriodic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, citric, maleic, glycollic, gluconic, gulonic, succinic, .arylsulfonic, e.g. p-toluenesulfonic acid and the like.

The pharmaceutically-unacceptable salts, while not useful for therapy, are valuable for use in the isolation and purification of these newly discovered compounds. Furthermore, they are useful for the preparation of the therapeutically valuable pharmaceutically-acceptable salts. Of this group, the more common salts include those formed with hydrofluoric and perchloric acids. Hydrofluon'de salts are particularly useful for the preparation of the pharmaceutically-acceptable salts. The hydrochloride salts, for example, may be prepared by the solution of the hydrofluoride salts in hydrochloric acid and crystallization of the hydrochloride salt thereby formed.

It is necessary that the active ingredient from a proportion of the composition such that a suitable dosage form will be obtained. Obviously, several dosage unit forms may be administered at about the same time. Although compositions with less than 0.005% by weight of active ingredient might be used, it is preferred to use com positions containing not less than 0.005% of the active ingredient; otherwise the amount of carrier becomes excessively large. Activity increases with the concentration of the active ingredient. The composition may contain 10, 50, 75 or an even higher percentage by weight of the active.

The person who administers the instant agents will determine the dosage which will be most suitable, and it will vary with the age, weight and response of the particular subject as well as with the nature and extent of the symptoms and the pharmacological characteristics of the particular agent to be administered. Generally, small doses will be administered initially, with a gradual increase in the dosage until the optimum level is determined. -It will often be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quantity administered parenterally. In general, a dosage level within the range of from about 0.2 to about 50 mg. of active ingredient per kilogram of body weight, administered in single or multiple dose units, will efiectively lower blood pressure. Of course, there can be individual cases where higher or lower dos- Analysis.-Calcd for C H N O (percent): C, 57.26; H, 5.49; N, 19.08. Found (percent): C, 56.88; H, 5.59; N, 19.00.

EXAMPLE III age levels are desirable, and such are within the scope of 5 Alkyl iscyaates are i .With z'dimethylamino'lt' this invention amino 6,7 dimethoxyquinazohne and 2-[4-(2-furoyl) The following examples are given to more fully illus prperaz1n-l-yl]-4-amino-6,7-d1methoxyqu1naz0l1ne accordtrate the persent invention. It is understood that these mg tofhe Procedures of Examples I and H to afiord the examples are for illustrative purposes only and are not followmg Products: to be considered as the only manner in which the instant 1 [2 (dimethy1amino 67 dimethoxy 4 quinazolinyl] invention may be embodied. 3 ethylurea EXAMPLE 1 1- [2- (dimethylamino -6,7-dimethoxy-4-quinazolinyl] 3-isopropylurea 1 [2 (dlmethylammo;rgzhdlfnethoxy'li'qumazohnyl1' 1-[Z-(dimethylamino)-6,7-climethoxy-4-quinazolinyl]- e y urea 3-n-hexylurea To a solution of 2-dimethylamino-4-amino-6,7-di- 1-[2-(4-[Z-furoyl]-l-piperazinyl)-6,7-dimethoxy-4- methoxyquinazoline (4.84 g., 0.0195 mole) in 150 ml. quinazolinyl]-3-ethylurea of pyridine was added methyl isocyanate (20.6 g., 0.36 1-[2-(4-[Z-fiuroyl]-l-piperazinyl)-6,7-dirnethoXy-4- mole). The mixture was heated in a pressure vessel at quinazolinyl]-3-isopropylurea 80 C. for 4 hours and then cooled in an ice bath. The 1-[2-(4-[2-furoyl]-1-piperazinyl)-6,7-dimethoxy-4-quinresulting crystalline material was collected by filtration, az0linyl]-3-n-hexylurea washed with ether and dried to afford the desired product, 4.76 g. (80%), M.P. 260-263 c. EXAMPLE IV Analysis.-Calcd for C H N O (percent): C, 55.07; The following l-(2-amino-4-quinazolinyl)ureas are pre- H, 6.27; N, 22.94. Found (percent): C, 55.39; H, 6.07; pared in the same manner as Examples I-III with the N, 22.95. appropriate 4-amino-quinazoline and isocyanate:

N /R1 R4-- \|N\ R2 R5 \/N I IHfiNHRa R1 R2 R3 Cs s- CaHa- CHs CaH5CHz- CaH5CHz CH3- CHz=CHCH-z OH2=CHCH2 CH3 (1 oH,=oH oH2)3 oH=oH- oH2)3 CH3 CsH CH-2 CsH5 CHad0.. 2HO-CsH.t- Same CHs- 4ClCaH4 d0 (CHa)2OH-CH2 (2-C4HaO)CH2 CH3- CHa 2-CHaO-CnH4 CaHs- (CH3)2CHCH2 H 5H5 Same CH3 CH H- CuH5CH2 CaH5CH2 CHs- C2H5O 02 5 3-BlCoH4 3-B1COH4 CH3 n-CsH- Il-C3H70 3CH OCaH4 3-CHaOCaH4 CHs- CzH O C2H5O 4-CsH130CaH4 4-CsH aO-CuH4 CH3- Same CH30 2, 4-(CsH1a)2CoHs ,4-(CoH1a)2CaHa- CH3 CHaO C2H5O 2, 4 Bl'2O6H5 2, 4BIzCaH CH3 C2H5O CH30- 3-CH CaH4 3-CH3CsH 0113- H Same. 3-01-0834 3-o1o6H4 CzH H 031110- 3-FCaH4 3-FCaHs- Same- CHaO- CH30 CsH5C2H4 CaH5CzH4 d0 CHsO- EXAMPLE II 65 EXAMPLE V 1- [2-(4- [2-furoyl] -1-pipefrazinyl) -6,7-dimethoXy- 4-quinazolinyl] -3 -methylurea 1-[2- (4-methy1-1-piperazinyl) -6,7-dimeth0Xy-4 quinazolinyl] -3 -methylurea Methyl isocyanate (20.6 g., 0.36 mole) is added to a solution of 2-(4-1nethyl-1-piperazinyl)-4-amino-6,7-dimethoxy quinazoline (6.11 g., 0.0195 mole) in 150 ml. of pyridine. The mixture is heated in a pressure vessel at C. for 7 hours and then cooled in an ice bath. The resulting precipitate is collected by filtration, Washed with ether and dried to afford the desired product.

3,574,212 7 8 EXAMPLE VI The following 1-(6,7-dimethoxy-4 quinazo1inyl)-3- The following 1- (Z-aminoA-quinazolinyl)ureas are premethylurea similar 1y prepared:

pared in the same manner as Example V using the appropriate 4-aminoquinazo1ine and isocyanate:

IMO e NH (III! NHRa Z R; R4 R5 Morpholino n-CaH1O n-CaI-I7 0- 4-al1y1-1-piperaziny1. 0 H3O (EH- 2,6-dipenty1morphol i- C3H O Same. Morpholino CHa- Same i-CaH-IO Piperidinm. 11-C4Hn CH30 CH30- 4-benzy1-1-p1p Same.. Same 11- l-azacyelooctyl n-CaH1 0- 4-pheny1-1-piperazinyl i-CaH7O- 4-methyl-1-piperaziny1. H- kpentyl-l-piperazinyl. H Cyclopropylamino. n-CaH1O Cycloheptylamino- CH3 0- Same.

4-acetyl-l-piperaziny 4-n-valeryl-l-piperazinyl 4-benzoyl-l-piperazinyL. 2,6-dimethylmorpholino 2,6-dip entylmorpholino l-azacyeloheptyl l-azaeyclooctyl Piperazin-1-y1-4-carb0xylie acid, isobutyl ester- Piperazin-l-yl--carboxylic acid, methyl ester OH Piperazin-l-yl-4-carboxy1ie acid, n-hexyl ester.-- 4-(2-methylallyl)-1-piperazinyl C Piperazin-l-yl-t-carboxylic acid, allyl ester- 4-benzyl-1-piperidino 4-n-propyl-1-piperidino 4-n-heptanoyl-1-piperazinyl 4-methyl-1'piperidino 4-n-pentyl-1-piperidino. Do. 4-n-butoxy-l-piperidino- D0. 4- (o-methy1pheny1) -1-piperazinyl Do. 4-(o-trifluoromethylbenz0y1)-1-piperazinyL. Do. 4-methoxy-1-piperidino Do. 4-phenyl-1-piperldino D0. 4-0-chlorophenyl-l-plperidin D0. 4-thenoyl-1-p iperazinyl D 0. 4-(p-methoxyphenyl)-1-piperaziny Do. 4-(o-methoxybenzoyl)-1-p1peraziny1 D0. 4-(m-methylbenzoyD-l-piperazinyL Do. 4-(o-methoxybenzoyD-l-piperazinyl Do. 4-(3,4,fi-trimethoxybenzoyl)-1-piperaziny1- Do. 4-(o-chlorophenyl)-1-piperazinyl Do. 4-(p-bromophenyl)-1-piperaziny1 D0. 4-(o-chlorobenzyl)-1-piperazinyl Do. 4-(obromobenzyl-l-piperazinyl D0. 4-trlfluoromethyl-l-piperazinyl "do .-d0 D0.

EXAMPLE v11 0,115

01130- N The following 1 (6,7 d1meth0xy-4-qu1nazohnyl)-3- 002C113 methylureas are prepared by the procedure of Example V; CH3O N I NHYJNHCH; N 01130- N NY 0 EXAMPLE VIII CH3O 1-[2-(4-ally1-1-piperazinyl)-6,7-dimethoxy-4- I quinazolinyl]-3-methylurea NHfiNHOm The procedure of Example V was repeated using an 0 equivalent amount of 2-[4-ally1-1-piperazinyl]-4-amino- 6,7-d1methoxyquinazoline. The reaction was conducted Y at 100 C. for 4 hours to afiord the desired product in CH 78.5% yield, M.P. 248250 C. 2 Analysis.Caled for C H N O' (percent): C, 59.05; H, 6.78; N, 21.75. Found (percent): C, 59.03; H, 6.62; N, 21.78. EXAMPLE IX 1-[2-(4-carbisobutoxy-1-piperazinyl)-6,7-dimethoxy- \o/ 4-quinazo1iny1] -3 -methylurea The procedure of Example V was repeated using an equivalent amount of 2-(4-carbisobutoxy-l-piperazinyl)- 4-amino-6,7-dimethoxyquinazoline. The reaction was conducted at 100 C. for 4 hours to afford the desired N product in 48% yield, M.P. 241-243 c.

Analysis.Calcd for C H N O (percent): C, 56.49; H, 16.77; N, 18.82. Found (percent): C, 56.39; H, 6.70; N, 18.83. 1

EXAMPLE X (2-dimethylamino-6,7-dimethoxy-4-quinazolinyl)urea To a suspension of 7.44 g. (0.3 mole) of 4-amino-2- dimethylamino-6,7-dimethoxyquinazoline in 30 ml. of warm water is added, with stirring, 2.75 ml. (0.33 mole) of concentrated hydrochloric acid (12 N). The resulting quinazolinyl)-3-methylurea (5 g.) in 90 ml. of a ethanolic solution of ethylamine is heated at 160 C. for 16 hours. The solvent and excess ethylamine are then evaporated, and the residue is recrystallized from methanol/water to afford the desired product.

EXAMPLE XIII The procedure of Example XII is repeated using appropriate quinazoline and isocyanate t0 alford the following compounds:

N R4- \|N\ R N R2 NH(||3NHR3 R1 R2 R3 R4 R5 (2-C4H3O)CH2 H CH3 CH3() CHaO- H- CHa H 0H30- i-Cl-CaHr- H- CH3 C'zHsO- H- 3,4-o12C@H3 H CHa 11-C3H7O- n-C H O- 2-HOCoHl- H CH3 i-OsH7O- HO(CH2)5 H0(CH2)J a- H 1-CaH1O 2-oH3ocflH. H- 0H3 0H30- CHaO- CF3CH2 H CH3 H- n-OaH O CF3CH2 H CH3- CH CH30- 2,4-(CHs)2CsHa H CH3 C2H5O Same. 2-CaH13CaH4 H- CH3 Same. D0. 2-CH3CuH4 H CH3 H C2H50 CaH5 H C2H5 CHaO Same. 2-HOCOH4 H Same H 015E110- 3-F0uH.- H- d0 CH3O CH3O H- H- do Same Same. CH3 H do ...do H- n-C5H11 H do do H- solution is placed in a porcelain evaporating dish, 1.98 /N\ g. (0.33 mole) of ammonium cyanate is added, and the R4- lz mixture is heated on the steam bath for 1 hour. The N liquid is allowed to cool, set aside at room temperature Ra for 1 hour, and then evaporated slowly to dryness over I a period of 23 hours. The crystalline residue is crushed NH%NHR3 finely, 30 ml. of water is added, and again the mixture 4 O is evaporated slowly. The residual powder 1s heated finally on the steam bath for 4-5 hours.

The resulting mixture of crude product and ammonium Z R; R4 R5 chloride is powdered finely and iusplended7 30 mil. gg g gl fii 8g g g of water. The mixture is warmed s ow y to wit v roxye y- -p r; a y stime--. ame.

4.5 4-hydrox entyl-l-piperazmyl n-C H .do H- mechamcal stirring, then allowed to cool to 35 C. and if?d,gg%ethyl lpipe,idmo ggjj 3E g Y XY- -piperi ino a 30- ame. the product is filtered wlth suction. 21% y d mxyethy1 1 piperidino UHF EXAMPLE XI 4-(4-hydroxybutyl)-l-piperidino. O2H5 H- De.

The procedure of Example X is repeated using an equivalent amount of appropriate quinazoline t0 atford the following products EXAMPLE XIV (2-ethylamino-6,7-dimethoxy-4- quinazolinyl) urea To a suspension of 2 chloro-4-amino-6,7-dimethoxy quinazoline (6.2 g., 0.03 mole) in 30 ml. of warm water is added, with stirring, 2.75 ml. (0.33 mole) of concentrated hydrochloric acid (12 N). The resulting solution is placed in a porcelain evaporating dish, 1.98 g. (0.33 mole) of ammonium cyanate is added, and the mixture is heated on a steam bath for one hour. The liquid is allowed to cool, set aside at room temperature for one hour, and then slowly evaporated to dryness over a period of 2-3 hours. The crystalline material is crushed finely, 30 ml. of water is added, and again the mixture is evaporated slowly. The residual powder is heated on a steam bath for an additional 4-5 hours, after which time it is finely powdered and again suspended in 30 ml. of water. The mixture is warmed slowly to 70 C. with stirring, then allowed to cool to 35 C. The resulting (2- chloro-6,7-dimethoxy-4-quinazolinyl)urea is collected by filtration.

A suspension of the (2-chloro-6,7-dimethoxy-4-quinazolinyl)urea (5 g.) in an ethanolic solution of ethylamine is heated at C. for 16 hours. The solvent and excess ethylamine are then evaporated, and the residue is recrystallized from methanol/water to afford the desired product.

1 1 EXAMPLE XV The procedure of Example XIV is repeated using appropriate quinazolines to afford the following compounds:

2 Rs- N NH $1) NH2 R1 2 R4 R5 CnHsCHr- H H C2l'I5O-- HOCHzCHz- HOCHzCHz- CHaO- CH30- H- H- Same Same.

EXAMPLE XVI Pharmaceutically-acceptable salts The hydrochloric acid addition salts of the products of Examples I-XII are prepared by mixing an alcoholic solution of each of said products with dilute hydrochloric acid and evaporating the resulting solution to dryness.

Additional acid addition salts of each of these porducts are similarly prepared by using aqueous solutions of the following acids in place of said hydrochloric acid: hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid, citric acid, phosphoric acid, maleic acid, tartaric acid and lactic acid.

EXAMPLE XVII Anti-hypertensive activity Hypotensive activity was measured in hypertensive conscious dogs with systolic blood pressure of at least 150 mm. Hg. The hypertension was induced by the method of Goldblatt et al., J. Exp. Med. 59, 347 (1934).

The systolic blood pressure was determined on the coccygeal artery according to the method of Prioli and Wynbury, J. Appl. Physiol. 15, 323 (1960) prior to drug administration and 2, 6 and 24 hours thereafter. The drugs were administered orally in the form of capsules, except as indicated.

The following hypotensive effects were noted:

wherein R and R are each selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, hydroxyalkyl having from 2 to 5 carbon atoms, phenyl, benzyl, phenylethyl, Z-furfuryl, 2,2,2-trifluoroethyl and cyclo alkyl having from 3 to 8 carbon atoms;

R is H or alkyl having from 1 to 6 carbon atoms;

R and R are each selected from hydrogen and alkoxy having from 1 to 3 carbon atoms, at least one of R and R being alkoxy;

Z is selected from the group consisting of morpholino,

l-azacycloheptyl, l-azacyclooctyl and piperazine of the formula:

where Y is selected from the group consisting of hydrogen, alkyl having from 1 t o 5 carbon atoms, hydroxyalkyl where alkyl has from 2 to 5 carbon atoms, alkanoyl having from 2 to 7 carbon atoms, allyl ,propargyl, Z-methylallyl, phenyl, benzyl, benzoyl, halobenzoyl and halophenyl where halo is chloro or bromo, trifluoromethylphenyl, methoxyphenyl, methylphenyl, methylbenzoyl, methoxybenzoyl, trifluoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl, 3,4, S-trimethoxybenzoyl, carboxylic acid alkyl ester Where alkyl has from 1 to 6 carbon atoms, carboxylic acid alkenyl ester Where alkenyl has from 3 to 6 carbon atoms; piperidino of the formula:

where X is hydrogen or phenyl, and X is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, al-koxy having from 1 to 4 carbon atoms, hydroxy, hydroxyalkyl where alkyl has from 2 to 5 carbon atoms, phenyl, and benzyl when X is hydrogen, and X is carboxylic acid alkyl ester where alkyl has from 1 to 6 carbon atoms when X- is phenyl; and the hydrofluoric acid and prechloric acid addition salts thereof, and the pharmaceutically acceptable mineral acid and organic acid addition salts thereof.

2. Compounds of claim 1 wherein R and R are each methoxy.

3. The compound of claim 1 of Formula I wherein R R and R are each methyl and R and R are each methoxy.

4. The compound of claim 1 of Formula II wherein R is methyl, R and R are each methoxy, and Z is 4-(2- furoyl)piperazin-1-yl.

5. The compound of claim 1 of Formula II wherein R is methyl, R and R are each methoxy and Z is 4-allylpiperazin-l-yl.

6. The compound of claim 1 of Formula 11 wherein R is methyl, R and R are each methoxy and Z is 4-carbisobutoxypiperazin-l-yl.

References Cited UNITED STATES PATENTS 2,884,423 4/ 1959 Wilkinson 260256.4

ALEX MAZEL, Primary Examiner R. I. GALLAGHER, Assistant Examiner U.S. Cl. X.R. 

